title: Diversity-oriented synthesis of macrocyclic peptidomimetics.
abstract: Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Isidro-Llobet
authors.forename: Tiffanie
authors.initials: T
authors.lastname: Murillo
authors.forename: Paula
authors.initials: P
authors.lastname: Bello
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: James T
authors.initials: JT
authors.lastname: Hodgkinson
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Martin
authors.initials: M
authors.lastname: Welch
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D047028:Macrocyclic Compounds; D057786:Peptidomimetics